Stereocontrolled synthesis and pharmacological evaluation of azetidine-2,3-dicarboxylic acids at NMDA receptors

Mangaleswaran Sivaprakasam, Kasper B. Hansen, Olivier David, Birgitte Nielsen, Stephen F. Traynelis, Rasmus P. Clausen, François Couty, Lennart Bunch

Research output: Contribution to journalArticlepeer-review

Abstract

The four stereoisomers of azetidine-2,3-dicaroxylic acid (L-trans-ADC, L-cis-ADC, D-trans-ADC, and D-cis-ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis-ADC enantiomers and one giving access to the two trans-ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([ 3H]CGP39653) at native NMDA receptors: L-trans-ADC showed the highest affinity (Ki = 70 μM) followed by the D-cis-ADC stereoisomer (21 μM). In contrast, the two analogues L-cis-ADC and d-trans-ADC were low-affinity ligands (> 700 and 90μM, respectively). Electrophysiological characterization of the ADC com-pounds at the four NMDA receptor subtypes NR7/NR2A, NR1/NR2B, NR1/NR2C, and NR7/NR2D expressed in Xenopus oocytes showed that L-trans-ADC displayed the highest agonist potency at NR1/NR2D (EC 50 = 50μM), which was 9.4-, 3.4-, and 7.9-fold higher than the respective potencies at NR7/NR2A-C. D-cis-ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium-range micromolar potencies (EC50 = 720 and 230 μm, respectively). A subsequent in silico ligand-protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site.

Original languageEnglish
Pages (from-to)110-117
Number of pages8
JournalChemMedChem
Volume4
Issue number1
DOIs
StatePublished - Jan 12 2009

Keywords

  • Conformational restriction
  • Enantioselectivity
  • Glutamate
  • NMDA
  • Receptors

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